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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

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YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression

Huapeng Li1, Qi Li2, Kyvan Dang1

  • 1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Cell Reports
|December 5, 2019
PubMed

Insights

This study reveals that Lats1/2 kinases suppress uveal melanoma (UM) formation. Activating YAP initiates UM, and combined YAP/TAZ and Ras/MAPK inhibition offers a new therapeutic strategy for UM.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Uveal melanoma (UM) is the most common primary ocular malignancy.
  • GNAQ/11 mutations are characteristic of UM.
  • Hippo/YAP and Ras/MAPK signaling pathways are implicated in UM pathogenesis downstream of GαQ/11.

Purpose of the Study:

  • To investigate the in vivo role of Hippo/YAP and Ras/MAPK pathways in uveal melanoma genesis.
  • To determine if Lats1/2 kinases suppress UM formation.
  • To explore therapeutic strategies targeting these pathways.

Main Methods:

  • Adeno-associated virus (AAV)-based ocular injection in mice to deliver Cre recombinase.
  • Genetic manipulation of Lats1/2, YAP, and Kras in mouse uveal melanocytes.
  • Assessment of UM initiation and progression.
  • In vitro studies on human UM cells.

Main Results:

  • Lats1/2 kinases suppress uveal melanoma formation in vivo.
  • Genetic activation of YAP, but not Kras, is sufficient to initiate UM.
  • YAP/TAZ activation cooperates with Kras to promote UM progression.
  • Dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress human UM cell growth.

Conclusions:

  • Lats-YAP/TAZ signaling is functionally significant in UM initiation and progression.
  • Combination inhibition of YAP/TAZ and Ras/MAPK presents a potential novel therapeutic strategy for uveal melanoma.
Keywords:
AAV ocular injectionHippo/YAPRas/MAPKdual inhibitionmouse modeltumor initiationtumor progressionuveal melanoma

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